2-alkylidene-3-keto-4-acylamidotetrahydrothiophene



Patented New 2, N43 I I Y 2-ALKYLmENE-3-KE'E0-d-ACYLAMIDO- TE'ERAHYDROTHIOEHENE Stanton A. Harris, Westfleld, and Karl Folkers, Plainfield, N. 5., assignors to Merck 8; 00., line,

Rahway, N. 3., a corporation of New Jersey No Drawing. Application September 16, 19%, Serial No. 554,452

' 20 Ciaima. (E. 26-329) ii I a FHCIE This invention is concerned generally with Boo R R00 RCO novel chemical compounds and processes of pre- I l paring the same; more particularly it relates to' I E E i novel compounds useful as intermediates in syn- I thesis of the growth-promoting factor, biotin. 5 g, s c=cmcm tc 09R claws-(340E940 02R Biotin is known to be one of the'isomers of (9a) (9b) the chemical compound 2-(4'-carboxy-butyl)- 3:4-m'eid0-tetrahydrothi0phene, having the empirical formula CmHmOaNzS, and the structural l formula: a v m catalyst 0 RC0 RCO HN--NE NE 5 v H tH on?! Bic-s JHC mom c memo 02H (113F843 HWHNUWR It is now found that this compound can be 10H: than n synthesized by reactions indicated as follows: NHZ NHz I NHI ITTH! H-C OzH XC-H ,OO2H g 03H 26 l (11) Err-SE CHr-S-CHaCOsH "kcmcmmmfl o (2) loom y l R003 0 T Boo V HN--Z|QH (12) NH NE oH---oH H-COQR K513 ctr-0 0,12 cm-s-cmcaowoafl Hrs-Gmoom Agra-Cmcofl 393 In the above formulae, R represents an alkyl,

( aryl or aryialhyl group; X, a halogen; and M an alkali metal or an alkaline earth metal.

The reactionsabove indicated are conducted 7, as follows: 2-amino-3-mercapto-propanoic acid RCO Rob (1) and chloroethanoic acid are condensed in an NH 0 L 0 v alkaline aqueous solution to form 2-amino-3- 4 H g l carboxymethylmercapto propanoic acid (2); H(|3 TE which is then treated with an acylating agent, m-s-cc 0,11 heat CH:S- H: such as an acyl halide, in an aqueous alkaline so- M lution to yield 2-acylamido-3-carboxymethylhre" capto-propanoic acid (3). This product is esterifled using a mineral acid catalyst to produce the diester (4) of the acid (3), and the diester is 5 treated with alkali metal alcoholate or an alkaline earth metal alcoholate to yield the 2-alkali R00 RC0 metal or the 2-alkaline earth metal derivative of i I I an ester of 2-carboxy-3-keto--aeylamido-tetrai 1510B NHOH P f hydrothiophene(5). This compound, when heat- CBI( Z gfi g 58 ed with a dilute mineral acid, is hydrolyzed and r o on decarboxylated to produce 3-keto-4-acylamido- H s C CHwHmC 2R Hrs OHwHmC a tetrahydrothiophene (6) which, when reacted lROM with 4-oarboxy=butanal ester in a lower aliphatic alcohol reaction medium containing piperidine and a lower aliphatic carboxylic acid, produces l (R C 0)n0 2-( 2!-carboalkoxy-butylidene)-3-keto-4-acylami- 3 do-tetrahydrothiophene (7) This product, when reacted with hydroxylamine yields an ester of the corresponding oxime, 2-(4'-carboxy-butylidene) -3-isonitroso-4-acylamidotetrahydrothiophene (8) which upon treatment with a mixture of zinc. a lower aliphatic acid and a lower aliphatic acid'anhydride, produces an equilibrium phene. This product is obtained as a mixture of stereoisomers, one of which is racemic biotin, from which upon resolution, is obtained the dextrorotatory isomer. biotin.

This invention is concerned with the novel class of compounds of which intermediate '7 above is a member, namely'the 2-alkylldene-3-keto-4- 'acyiamido-tetrahydrothiophenes, particularly the class of such compounds wherein the 2-alkylidine substituent is an omega-carboxy, omega-carboalkoxy, omega-carboaryloxy, or an omega-carboarylalkoxy-alkylidine. Members of this last mentioned class of compounds are represented by the general formula:

wherein R is an acyl group, R is'of the class consisting of alkyl, aryl and aryialkyl groups, and n is a small integer. In the general classof 2-alkylidene compounds, the z-substituent in this formula is CnH-zn.

According to the present invention, compounds of the class represented by the abov general formula are prepared by a process indicated as follows:

by e (pipcndlne acetate catalyst) wherein R, R and n have the meaning assigned above. It is presently preferred to conduct the reaction at about room temperature (30 C.) under essentially neutral conditions and using 'a substantiall inert organic solvent such as alcohol as a reaction medium.

The starting material, 3-keto-4-acylamldotetrahydrothiophene can be prepared as indi boxyl group with a thionyl halide and catalytical- Ly reducing the product by the Rosenmund reacggrii to obtain the desired omega-carboxy alde- For example, 4-carbomethoxy-butyral-1 is prepared as follows. A mixture oi about 412 g. of 1:3-dicarboxy-propane and 237 g. of methanol is heated about 2 hours ona steam bath, and the half-ester (B. P. 158-165 C./23 mm.) is removed by fractionation and reacted with about 400 g. of thionyl chloride, thei mixture being heated on the steam bath to complete the reaction. The mixture is fractionated and a fraction boiling at 110-113 C. under 23 mm. pressure is collected. About 330 g. of this fraction in 1200 00.01 Xylene is hydrogenated under reflux in a closed vessel, using a palladium on barium sulfate catalyst. until evolution of hydrogen chloride ceases. The mixture is then cooled to room temperature, filtered, the solvent is removed under reduced pressure and the residue is fractionated at recated above and as described in detail in concurrently filed applications, Serial Nos. 554,449, 554,450, 554,451, 554,458; the reaction product, when n is 3, namely 2-(4'-carboalkoxy-butylidene) -3-keto-4-acylamido tetrahydrothiophene,

is an intermediate usefulin synthesis of biotin as indicated above and as described in detail in concurrently filed applications, Serial Nos. 554453, 554,454, 554,455, 554,456 and 554,457, The starting material omega-carboxy-aiiphatic aldehyde can be prepared bytreating a selected aliphatic dicarboxylic acid with an alkylating agent to form a mono-ester, reacting the un'esterified carduced pressure, the 4-carbomethoxy-butyral-l being collected in the traction boiling at loo-103 C. under 23 mm. pressure. Analogous compounds are prepared in like manner.

Among the 3-keto-4-acylamido-tetrahydrothiophenes which can be utilized in the process according to this invention are those wherein the acyl group is acetyl, propionyi and benzoyl; among the aldehydes which can be used are those represented by the general formula R(CH2)1: CHO wherein R is hydrogen, carboxy, carboalkoxy, carboaroxy, carboarylalkoxy or a group other than an aldehyde group readily converted to carboxy; and n is a small integer not exceeding 10.

The following examples illustrates methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

Example 1 0 010 H;

H: C sHtO O (l; C disc 0 I H 0 I f i l il p per ne CH-G:0 acetate CHC:0 catalyst Ha-S-CH: 4 H:SC:CH(CH:)CO1CH1 To a solution of about 22 g. of 3-keto-4-benzamide-tetrahydrothiophene in 200 cc. of ethanol isadded about 13 g. of 3-c arbomethoxy-propanal-l and, as a catalyst, about 1.5 cc. of piperidine and about 0.9 cc. of acetic acid (glacial). The reaction mixture is allowed to stand at room temperature for about four hours, small amounts of piperidine being added from time to time to maintain the solution substantially neutral. The solution is then cooled and precipitated 2- (3'-carbomethoxy-propylidene) -3-keto- 4-benzamido tetrahydrothiophene (M. P. 141- 143 C.) is recovered and purified by recrystallization from ethanol.

carbomethoxy group is converted to a carboiwl a l-tacos which is recovered by filtration. When ,this

product is heated 'with dilute mineral acid the group, yielding the free acids (M. P, 152- -'4 6.).

- Upon treatment of 2-(4'-carbomethoxy-butylidene) -3-keto -4-benzamido-tetrahydrothiophene with p-nltrophenyl hydrazine the corresponding p-nitrophenylhydrazone (M. P. 154-6 C.) is obtained and similarly treatment with .2z4-dinitrophenylhydrazine yields the .2z4-dinitrophenylhydrazone (M. P. 181 -185 C'.)

Example 3' C H:(C HihC HO piparidlne acetate catalyst nr-s-domcnmon.

To a solution of about 17 g. of 3-keto-4-benzamido-tetrahydrothiophene in 157 cc. of absolute ethanol is added about 11 g. of 5-carboethoxypentanol-l, and 3 cc. of piperidine and 1.8 cc. of acetic acid (glacial) as a catalyst. The solution is allowed to stand at room temperature for about four hours, small quantities of piperidine being added from time to time to maintain the neutrality of the solution. The solution isthen cooled, filtered and concentrated. In cooling this concentrate, the 2-(5'-carboethoxy-pentyli dene) -3-keto -4-benzamido-tetrahydrothiophene (M. P. 118-119 C.) which separates is recovered by filtration and recrystallized irom ethanol.

In like manner similar compounds having acylamido substituents difierent from the benzamido group can be condensed with aliphatic -aldehydes to yield corresponding products ior example, 3- ireto-4-acetylamido-tetrahydrothiophene can be condensed with 4-carbomethoxy-butanal-l to obtain 2- (4-carbomethoxy-butylldene) -8-keto- 4- aeetylamido-tetrahydrothiophene.

It also will be apparent to those versed in this art that the above described condensation reae-. tion can be applied to other esters oi the selected aldehydes, includingjboth lower and higheralkyl, aryl or aralkyl esters. For example, the conden-j sation of.4-carbophenoxy-butanal-1 and 3-keto- 4abenzamido-tetrahydrothiophene yields, 2-44- carbophenoxy-butylidene) 3 -keto-4-benzamidotetrahydrothiophene.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof and the invention is to be limited only by the appended claims. What is claimed is: a

1. A compound selected from the class which I consists of 3-keto-4-acylamido-tetrahydrothiophenes having a 2-position substituent selected from the class consisting of alkylidene; omegacarboxy-alkylidene, omega-carboalkoxy-alkylidene, omega-carboaroxy-alkylidene and omega-,- carboaryi-alkoxy aikylidene 2. A compound represented by the formula:

aNn

n---o=o om-s-czcmcmhcola' B is an alkyl radical,

wherein R is an acyl group, and n is a small integer.

3. 2-(4'-carbomethoxy butyli benzamido-tetrahydrothiophene.

4. The process that comprises reacting an allphatic aldehyde with a 3-keto-4-aeylamido-tetrahydrothiophene, said reaction being carried out under substantially neutral conditions and in the presence of an organic solvent, to produce a 2- alkylidene-3-keto-4 acylamido tetrahydrothiophene.

5. The process that comprises reacting an allphatic aldehyde with a 3-keto-4-acylamido-tetrahydrothiophene, said reaction being carried out in solution in a substantially inert organic solvent under substantially neutral conditions and in the presence of piperidine acetate as a' catalyst, to produce a 2-alkylidene-3-keto-4-acylamido-tetrahydrothiophene.

6. The process that comprises reacting an omega-carboalkoxy-aliphatic aldehyde with a 3- keto-4-acylamido-tetrahydrothiophene, said reaction being carried out under substantially neutral conditions and in the presence of an organic dene) -3-keto-4- solvent, to produce a 2-(omega-carboalkoxy-alkylidene) -3-keto a acylamido-tetrahydrothiophene. j

'7. The process that comprises reacting on omega-carboalkoxy-aliphatic aldehyde with'a 3- ketoi-acylamido--tetrahydrothiophene, said reaction being carried outin solution in a substantially inert organic solvent under substantially. neutral conditions and in the presence of piperidine acetate as a catalyst, to produce a 2-(omegacarboalkoxy-alkylldene) 3 keto 4-acylamidotetrahydrothiophene.

8. The process that comprises reacting a 4- carboalkoxy-butanal-l with a 3-keto-4-acylamido-tetrahydrothiophene, said reactlonbeing carried out under substantially neutral conditions and in the presence of an organic solvent, to produce a 2-(4'-carboalkoxy-butylidene) -8- keto-4-aeylamido-tetrahydrothiophene.

9. The process that comprises reacting a 4- carboaikoxypbutanal-l with a 3-keto-4-acy1- amido-tetrahydrothiophene, said reaction being carried out in solution in a substantially inert organic solvent under substantially neutral conditions and in the presence or piperidine acetate as a catalyst, to produce a 2-(4'-carboalkoxybutylidene) -3-keto-4 acylamido-tetrahydrothiophene.

10. The process that comprises reacting a4- carboalkoxy-butanal-l with 3-keto-4-benzamidotetrahydrothiophene, said reaction being carried out under substantially neutral conditions and in the presence of an organic solvent. to produces. 2-(4' carboalkoxy butylidene) -3-keto-4-benzamido-tetranvdrothiophene.

11. 2-(4'-carboxy butylidene) -3-keto-4-ben2- amido tetrahydrothiophene.

12. A compound represented by the formula:

wherein R is an acyl group, and Ella an alkyl radical.

13. A compound represented by the formula:

BNH

JJH-C:O

ni-s-owmcmpcom' wherein R is an acyl group, and R is an alkyl radical. I

14. A compoungnrepresented by the formula:

RNH

n--c= cnhs-ozcmcrnnc om wherein R is an acyl group, and R is an aryl radical.

15. A compound represented by the formula:

wherein is an acyl group. and R is an aralkyl radical.

16. A compound represented by the formula:

wherein R is an acyl group, and R is an alkyl radical.

17. A compound represented by the formula: CJMIJO NH JIH' C:O oars-om mcznncom wherein R is an alkyl radical.

1 18. The process which comprises reacting 4- carbomethoxy-butanal-l with 3-keto-4-benzam'ido-tetrahydrothiophene, said reaction being carried out in solution in a substantially inert organic solvent under substantially neutral conditions and in the presence 01" piperidine acetate ditions and in the presence of piperidine acetate as a catalyst, to produce the corresponding 2-(5'- carboalkoxy-propylidene) 3 lreto-4-acylamidotetrahydrothiophene.

STANTON A. HARRIS. KARL FOLKERS.

REFERENCES CITED The following references are of record in the tile of this patent:

v UNITED STATES PATENTS Number Name Date 2,228,452 Gleason Jan. 14, 1941 2,336,916 Arnold Dec. 14, 1943 Certificate of Correction Patent No. 2,452,653. November 2, 1948, STANTON A. HARRIS ET AL.

It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows:

Column 1, Formula (5), extreme lower left hand portion thereof, for

CH -84300 11 read C'H 00O,R

column 2, Formula (9b), lower right hand portion thereof, for

column 3, line 12, for the words of if read or ii); column 4, Example 1, lefthand portion thereof, for

0:0 CH1 read 43H! same Example 1, right hand portion thereof, for

d 0:0 0:011 hCH column 4, Example 2, left hand portion thereof, for CH=--'-C:O read 0H-C':0; same Example 2, right hand portion thereof, for

0:011 (non and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Ofiice.

Signed and sealed this 24th day of May, A. D. 1949.

THOMAS F. MURPHY,

Assistant Oommz'ssioner of Patents. 

